According to the American Cancer Society ovarian cancer is expected to account for over 22,000 new cancer diagnoses and more than 14,000 deaths in 2013 in the US alone. Of the gynaecologic malignancies, ovarian cancer has the highest mortality rate. In early stages of the disease, ovarian cancer is nearly asymptomatic. Hence, a large portion of the patients present with clinically advanced stages of ovarian cancer. However, the 5-year survival rate for patients diagnosed with early-stage disease is often >90%, but it is <20% for advanced-stage disease, underscoring the importance of early detection.
Current diagnosis of ovarian cancer relies on pelvic exam, transvaginal ultrasonography, (TVS), abdominal ultrasonography, and exploratory or diagnostic laparoscopy. The most commonly used biomarker for clinical screening and prognosis in patients with ovarian cancer is ovarian cancer antigen 125 (CA125) (Coticchia et al. (2008), J. Natl. Compr. Canc. Netw. 6(8):795-802). Serum CA125 levels are elevated in ≈80% of patients with advanced-stage epithelial ovarian cancer but are increased in only 50-60% of patients with early-stage disease. Serum CA125 levels may be falsely elevated in women with any i.p. pathology resulting in irritation of the serosa of the peritoneum or pericardium, uterine fibroids, renal disorders, and normal menses. Moreover, serum CA125 levels do not predict the outcome of cytoreductive surgery in patients with advanced epithelial ovarian cancer. Further biomarkers include, for example, Human Epidymis Protein 4 (HE4) and Mesothelin (Sarojini et al. (2012), Journal of Oncology 102, Article ID 709049). Severeness of ovarian cancer is categorized by the grade and stage of tumorization. This nowadays can only be performed by evaluation of the tumors under or after surgical treatment or by combining marker evaluation and (histological) evaluation of tissue. Staging is very important because ovarian cancers have different prognosis at different stages and may be treated differently. The accuracy of the staging may determine whether or not a patient will be cured. If the cancer isn't accurately staged, then cancer that has spread outside the ovary might be missed and not treated. Once a stage has been given it does not change, even when the cancer comes back or spreads to new locations in the body.
Ovarian cancer staging is by FIGO staging system uses information obtained after surgery, which can include a total abdominal hysterectomy, removal of (usually) both ovaries and fallopian tubes, (usually) the omentum, and pelvic (peritoneal) washings for cytopathology. The AJCC stage is the same as the FIGO stage. The AJCC staging system describes the extent of the primary tumor (T), the absence or presence of metastasis to nearby lymph Nodes (N), and the absence or presence of distant Metastasis (M).
Stage I Limited to One or Both Ovaries                IA involves one ovary; capsule intact; no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings        IB involves both ovaries; capsule intact; no tumor on ovarian surface; negative washings        IC tumor limited to ovaries with any of the following: capsule ruptured, tumor on ovarian surface, positive washings        
Stage II Pelvic Extension or Implants                IIA extension or implants onto uterus or fallopian tube; negative washings        IIB extension or implants onto other pelvic structures; negative washings        IIC pelvic extension or implants with positive peritoneal washings        
Stage III peritoneal implants outside of the pelvis; or limited to the pelvis with extension to the small bowel or omentum                IIIA microscopic peritoneal metastases beyond pelvis        IIIB macroscopic peritoneal metastases beyond pelvis less than 2 cm in size        IIIC peritoneal metastases beyond pelvis >2 cm or lymph node metastases        
Stage IV Distant Metastases to the Liver or Outside the Peritoneal Cavity
Para-aortic lymph node metastases are considered regional lymph nodes (Stage IIIC). As there is only one para-aortic lymph node intervening before the thoracic duct on the right side of the body, the ovarian cancer can rapidly spread to distant sites such as the lung.
The AJCC/TNM staging system includes three categories for ovarian cancer, T, N and M. The T category contains three other subcategories, T1, T2 and T3, each of them being classified according to the place where the tumor has developed (in one or both ovaries, inside or outside the ovary). The T1 category of ovarian cancer describes ovarian tumors that are confined to the ovaries, and which may affect one or both of them. The sub-subcategory T1a is used to stage cancer that is found in only one ovary, which has left the capsule intact and which cannot be found in the fluid taken from the pelvis. Cancer that has not affected the capsule, is confined to the inside of the ovaries and cannot be found in the fluid taken from the pelvis but has affected both ovaries is staged as T1b. T1c category describes a type of tumor that can affect one or both ovaries, and which has grown through the capsule of an ovary or it is present in the fluid taken from the pelvis. T2 is a more advanced stage of cancer. In this case, the tumor has grown in one or both ovaries and is spread to the uterus, fallopian tubes or other pelvic tissues. Stage T2a is used to describe a cancerous tumor that has spread to the uterus or the fallopian tubes (or both) but which is not present in the fluid taken from the pelvis. Stages T2b and T2c indicate cancer that metastasized to other pelvic tissues than the uterus and fallopian tubes and which cannot be seen in the fluid taken from the pelvis, respectively tumors that spread to any of the pelvic tissues (including uterus and fallopian tubes) but which can also be found in the fluid taken from the pelvis. T3 is the stage used to describe cancer that has spread to the peritoneum. This stage provides information on the size of the metastatic tumors (tumors that are located in other areas of the body, but are caused by ovarian cancer). These tumors can be very small, visible only under the microscope (T3a), visible but not larger than 2 centimeters (T3b) and bigger than 2 centimeters (T3c). This staging system also uses N categories to describe cancers that have or not spread to nearby lymph nodes. There are only two N categories, N0 which indicates that the cancerous tumors have not affected the lymph nodes, and N1 which indicates the involvement of lymph nodes close to the tumor. The M categories in the AJCC/TNM staging system provide information on whether the ovarian cancer has metastasized to distant organs such as liver or lungs. M0 indicates that the cancer did not spread to distant organs and M1 category is used for cancer that has spread to other organs of the body.
The AJCC/TNM staging system also contains a Tx and a Nx sub-category which indicates that the extent of the tumor cannot be described because of insufficient data, respectively the involvement of the lymph nodes cannot be described because of the same reason. The ovarian cancer stages are made up by combining the TNM categories in the following manner:
Stage I: T1+N0+M0; IA: T1a+N0+M0; IB: T1b+N0+M0; IC: T1c+N0+M0;
Stage II: T2+N0+M0; IIa: T2a+N0+M0; IIB: T2b+N0+M0; IIC: T2c+N0+M0;
Stage III: T3+N0+M0; IIIA: T3a+N0+M0; IIIB: T3b+N0+M0; IIIC: T3c+N0+M0 or any T+N1+M0;
Stage IV: Any T+ Any N+M1
In addition to being staged, like all cancers ovarian cancer is also graded. The histologic grade of a tumor measures how abnormal or malignant its cells look under the microscope. There are four grades indicating the likelihood of the cancer to spread and the higher the grade, the more likely for this to occur. Grade 0 is used to describe non-invasive tumors. Grade 0 cancers are also referred to as borderline tumors. Grade 1 tumors have cells that are well differentiated (look very similar to the normal tissue) and are the ones with the best prognosis. Grade 2 tumors are also called moderately well differentiated and they are made up by cells that resemble the normal tissue. Grade 3 tumors have the worst prognosis and their cells are abnormal, referred to as poorly differentiated.
Cancer staging can be divided into a clinical stage and a pathologic stage. In the TNM (Tumor, Node, Metastasis) system, clinical stage and pathologic stage are denoted by a small “c” or “p” before the stage (e.g., cT3N1M0 or pT2N0). Clinical stage is based on all of the available information obtained before a surgery to remove the tumor. Thus, it may include information about the tumor obtained by physical examination, radiologic examination, and endoscopy. Pathologic stage adds additional information gained by examination of the tumor microscopically by a pathologist.
Because they use different criteria, clinical stage and pathologic stage often differ. Pathologic staging is usually considered the “better” or “truer” stage because it allows direct examination of the tumor and its spread, contrasted with clinical staging which is limited by the fact that the information is obtained by making indirect observations of a tumor which is still in the body. However, clinical staging and pathologic staging still has to be complemented by each other. Not every tumor is treated surgically, therefore pathologic staging is not always available. Also, sometimes surgery is preceded by other treatments such as chemotherapy and radiation therapy which shrink the tumor, so the pathologic stage may underestimate the true stage.
In the minority of cases (5-10 percent) cancers are caused by an altered gene that is inherited. The abnormal growth, invasive properties and treatment resistance of the other 90-95 percent of cases are caused by acquired mutated genes or misregulated genes; i.e. they are not inherited and hence are unique to the developing tumor. Such abnormalities may affect many aspects of cell behaviour including the control of expression of other genes (epigenetic regulators). In addition risk factors can be present which are thought to be associated with the acquiring of cancer. Risk factors can be subdivided into those that can be altered and those that cannot. Examples of lifestyle factors that appear to affect the risk of cancer include smoking, exercise, weight, and alcohol use. Examples of risk factors that are not modifiable include age, gender, and family history. While there is sometimes a correlation between the type of cancer and exposure to certain toxins (such as lung cancer and smoking), most of the time the cause of cancer remains a mystery.
Although cancer often appears suddenly, most cancers grow slowly and remain without symptoms for several years. Hence, they may be advanced before they got detected. A cancer that has acquired aggressive properties, however, can seem to appear out of nowhere and cause death within months. Unfortunately, very little is known about the biologies that explain these different behaviours and outcomes.
If solid tumours are benign (harmless) and stay in their place of origin, they can generally be removed and pose no long-term threat. However, solid tumours that have acquired aggressive properties are able to spread (metastasize) via the blood or lymphatic (immune) systems to another part of the body. Once cancers metastasize the prognosis for the patient becomes poor, but why some tumours metastasize and others do not is still a mystery.
Staging is an important part of cancer diagnosis because it can be used to guide therapeutic decisions based on historical experience of particular outcomes after different treatments. In the TNM system of staging, the combination of the tumour size (T), the number of lymph nodes involved (N) and whether metastases are detectable (M) provides details which place the overall stage of the cancer at 0, I, II, III or IV. Some cancers also have particular cell surface receptors that give them a growth advantage, and knowing the receptor status can provide an even more in-depth assessment of the cancer's stage. In addition to staging factors, the likely outcome (or prognosis), may also be affected by the age, and health status of an individual. This staging system is used for most forms of cancer, except brain tumors and hematological malignancies. For solid tumors, TNM is by far the most commonly used system, but it has been adapted for some conditions.
However, there is a need for improved tools for the diagnosis, early detection; staging, grading and prognosis of cancer, e.g. a solid organ cancer, like ovarian cancer, squamous cell cancer, and metastatic cancer. In particular there is a need for predicting response to a cancer treatment.
The inventors found that the level of autoimmuneantibodies is a well suited predictor for the diagnosis, early detection, staging, and grading of tumors, Furthermore, it is possible to predict whether a patient to be treated or being treated for cancer will respond to said treatment. The invention hence solves the outlined problems and overcomes the drawbacks of the state of the art.